Processes for the preparation of 1-aryl-5-alkyl pyrazole compounds

Abstract

Provided are improved processes for the preparation of 1-aryl pyrazole compounds of formula (I) and (IB): which are substituted at the 5-position of the pyrazole ring with a carbon-linked functional group. The process described are efficient and scalable and do not utilize hazardous sulfenyl halide reagents.

We claim:  
     
       1. A process for preparing a 1-aryl-5-alkyl pyrazole compound of formula (IB): 
       
         
           
           
               
               
           
         
         wherein: 
         R 1b  is hydrogen, cyano, halogen, R 8b , formyl, —CO 2 H, —C(O)R 8b , —C(O)OR 8b , —C(O)NR 9b R 10b  or —C(S)NH 2 ; 
         R 2b  is—S(O) m R 11b ; 
         R 3b  is alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, halocycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, R 8b NH, (R 8b ) 2 N, R 8b O, R 8b S or R 8b C(O)CH 2 — wherein each alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl or heteroaryl group may optionally be substituted by one or more of halogen, hydroxy, alkoxy, alkoxyalkoxy, amino, alkylamino, dialkylamino, nitro, cyano or —C(S)NH 2 ; 
         R 4b , R 5b , R 7b  and R 13b  are each independently hydrogen, halogen, alkyl, haloalkyl, cyano or nitro; 
         R 6b  is halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, nitro, —C(O)R 12b ,—S(O) n R 12b  or SF 5 ; 
         W is nitrogen or C—R 13b ; 
         R 8b  is alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, halocycloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heterocyclyl or heteroaryl; 
         R 9b  and  R10b  are independently hydrogen, alkyl, haloalkyl, hydroxy or alkoxy; 
         R llb  is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl or halocycloalkyl; 
         R 12b  is alkyl or haloalkyl; 
         m is 0, 1 or 2; and 
         n is 0, 1 or 2; 
         which comprises the steps: 
         step (i) reacting a compound of formula (IIB): 
       
       
         
           
           
               
               
           
         
         wherein 
         R 1b  is hydrogen, cyano, halogen, R 8b , formyl, —CO 2 H, —C(O)R 8b , —C(O)OR 8b , —C(O)NR 9b R 10b  or —C(S)NH 2 ; 
         R 2b  is—S(O) m R 11b ; 
         R 4b  is hydrogen, halogen, alkyl, haloalkyl, cyano or nitro; 
         R 5b  is hydrogen, halogen, alkyl, haloalkyl, cyano or nitro; 
         R 6b  is halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, nitro, —C(O)R 12b , —S(O) n R 12b  or SF 5 ; 
         R 7b  is hydrogen, halogen, alkyl, haloalkyl, cyano or nitro; 
         W is halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, nitro, —C(O)R 12b , —S(O) n R 12b  or SF 5 ; and 
         Q is iodo, bromo, chloro or a haloalkylsulfonate group; 
         with a compound of formula (IIc): 
         R-M (IIc) 
         wherein 
         R is alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl or heterocyclyl, wherein each alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl or heterocyclyl group may optionally be substituted with one or more halogen, hydroxy, alkoxy, alkoxyalkoxy, amino, alkylamino, dialkylamino, nitro, cyano or —C(S)NH 2  groups; 
         M is MgX, ZnX, RZn, BY 2 , BF 3  or SnR′ 3 ; 
         X is iodo, bromo or chloro; 
         Y is OH or alkoxy, or each Y may be an alkoxy group which is part of a glycol derivative Y—(CR″R′″) a —Y where R″ and R′″ are independently hydrogen or C 1 -C 3  alkyl and a is 2, 3 or 4; and 
         R′ is alkyl or haloalkyl; 
         or 
         reacting the compound of formula (IIB) with R 8b NH 2 , (R 8b ) 2 NH, R 8b OH, R 8b SH or an enolate anion R 8b C(O)CH 2   − , wherein R 8b  is as defined above for the compound of formula (IB); 
         in the presence of a transition metal catalyst to form the compound of formula (IB); 
         step (ii) wherein if R 1b  in the compound of formula (IB) is —C(O)OR 8b  or —C(O)NR 9b R 10b , optionally converting the —C(O)OR 8b  or —C(O)NR 9b R 10b  groups to cyano, hydroxyalkyl, aminoalkyl, dialkylaminoalkyl, formyl, —C(O)R 8b  or —C(S)NH 2 , wherein R 8b , R 9b  and R 10b  are as defined above for the compound of formula (IB), via functional group modification; and 
         step (iii) optionally oxidizing the group —S(O) m R 11b  where m is 0 or 1, to form the compound of formula (IB); 
         wherein the sequence of steps ii) and iii) may be interchanged. 
       
     
     
       2. The process of  claim 1 , wherein the compound of formula (IIB) wherein Q is I, Br or Cl, is prepared by reacting a compound of formula (IIIB): 
       
         
           
           
               
               
           
         
         wherein R 1b  is hydrogen, cyano, halogen, R 8b , formyl, —CO 2 H, —C(O)R 8b , —C(O)OR 8b , —C(O)NR 9b R l0b  or —C(S)NH 2 ; 
         R 2b  is —S(O) m R 11b ; 
         R 4b  is hydrogen, halogen, alkyl, haloalkyl, cyano or nitro; 
         R 5b  is hydrogen, halogen, alkyl, haloalkyl, cyano or nitro; 
         R 6b  is halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, nitro, —C(O)R 12b , —S(O) n R 12b  or SF 5 ; 
         R 7b  is hydrogen, halogen, alkyl, haloalkyl, cyano or nitro; and 
         W is nitrogen or C—R 13b ; 
         with a source of Br, Cl or I and a nitrite compound T-ONO; 
         wherein T is hydrogen or alkyl, or a salt thereof. 
       
     
     
       3. The process of  claim 1 , wherein the transition metal catalyst is a palladium catalyst. 
     
     
       4. The process of  claim 2 , wherein T-ONO is sodium nitrite, isopentyl nitrite, or tert-Butyl nitrite. 
     
     
       5. The process of  claim 1 , wherein Q is bromo. 
     
     
       6. The process of  claim 1 , wherein M is ZnX or RZn. 
     
     
       7. The process of  claim 1 , wherein M is BY 2 . 
     
     
       8. The process of  claim 7 , wherein Y is hydroxy. 
     
     
       9. The process of  claim 1 , wherein R 3b  and R are methyl. 
     
     
       10. The process of  claim 1 , wherein in step (i) the compound of (IIB) is reacted with a compound of (IIc) wherein M is BY 2  , and wherein the process further comprises addition of a base to the reaction mixture. 
     
     
       11. The process of  claim 10 , wherein the base is an alkali metal hydroxide or an alkali metal carbonate. 
     
     
       12. The process of  claim 3 , wherein the palladium catalyst is selected from (Ph 3 P) 4 Pd, (Ph 3 P) 2 PdCl 2 , (CH 3 CN) 2 PdCl 2 , Pd 2 (dba) 3  or (dppf)PdCl 2 . 
     
     
       13. The process of  claim 2 , wherein the compound of formula (IIIB) is fipronil. 
     
     
       14. The process of  claim 4 , wherein T-ONO is sodium nitrite and the source of Br is HBr. 
     
     
       15. A process for preparing a 1-aryl-5-alkyl pyrazole compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  and R 3  are each independently hydrogen, cyano, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkenyl, alkynyl, formyl, aryl, heterocyclyl, heteroaryl, —C(O)R 8 , —C(O)OR 8 , —C(O)NR 9 R 10  or —C(S)NH 2 , wherein each alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl or heteroaryl group may optionally be substituted by one or more of halogen, hydroxy, alkoxy, alkoxyalkoxy, amino, alkylamino, dialkylamino, alkyl or haloalkylthio; alkyl or haloalkyl sulfinyl; alkyl or haloalkyl sulfonyl; nitro, cyano and —C(S)NH 2 ; 
         R 2  is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl or halocycloalkyl; 
         R 4 , R 5 , R 7  and R 12  are each independently hydrogen, halogen, alkyl, haloalkyl, cyano or nitro; 
         R 6  is halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, nitro, —C(O)R 11 , —S(O) m R 11  or SF 5 ; 
         Z is nitrogen or C—R 12 ; 
         R 8  is alkyl, haloalkyl, cycloalkyl or halocycloalkyl; 
         R 9  and R 10  are independently hydrogen, alkyl, haloalkyl, hydroxy or alkoxy; 
         R 11  is alkyl or haloalkyl; 
         n is 0, 1 or 2; and 
         m is 0, 1 or 2; 
         which comprises the following steps: 
         step (i) reacting a disulfide compound of formula (II) with an arylhydrazine of formula (III) 
       
       
         
           
           
               
               
           
         
         wherein R 1  and R 3  are each independently hydrogen, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkenyl, alkynyl, formyl, aryl, heteroaryl, —C(O)R 8 , —C(O)OR 8 , —C(O)NR 9 R 10  or —C(S)NH 2 , wherein each alkyl, cycloalkyl, alkenyl, alkynyl, aryl or heteroaryl group may optionally be substituted by one or more of halogen, hydroxy, alkoxy, alkoxyalkoxy, amino, alkylamino, dialkylamino, alkyl or haloalkylthio; alkyl or haloalkyl sulfinyl; alkyl or haloalkyl sulfonyl; nitro, cyano and —C(S)NH 2 ; 
         and R 4 , R 5 , R 6 , R 7  and Z are as defined for the compound of formula (I), to form a pyrazole disulfide of formula (IV) 
       
       
         
           
           
               
               
           
         
         wherein R 1 , R 3  R 4 , R 5 , R 6 , R 7  and Z are as defined for the compound of formula (I); 
         step (ii) reacting the compound of formula (IV) with a compound of formula (V)
   R 2 -LG  (V)
 
 
         wherein R 2  is as defined above for the compound of formula (I) and LG is a leaving group to form a compound of formula (VI) 
       
       
         
           
           
               
               
           
         
         step (iii) wherein if in the compound of formula (VI), R 1  or R 3  are —C(O)OR 8  or —C(O)NR 9 R 10 , optionally converting the —C(O)OR 8  or —C(O)NR 9 R 10 groups in the compound of formula (VI) to cyano, hydroxyalkyl, aminoalkyl, dialkylaminoalkyl, formyl, —C(O)R 8  or —C(S)NH 2 ; and 
         step (iv) optionally oxidizing the —SR 2  to form the compound of formula (I); 
         wherein the sequence of steps (iii) and (iv) may be interchanged. 
       
     
     
       16. The process of  claim 15 , wherein the disulfide of formula (II) is formed by reaction of the diketone of formula (VII) 
       
         
           
           
               
               
           
         
         with a disulfide dihalide reagent. 
       
     
     
       17. The process of  claim 15 , wherein in step ii) the reaction of the compound of formula (IV) with the compound of formula (V) is carried out in the presence of a reducing agent. 
     
     
       18. The process of  claim 17 , wherein the reducing agent is tetrakis(dimethylamino)ethylene, sodium borohydride, sodium dithionite, sodium hydroxymethanesulfinate, zinc hydroxymethanesulfoninate, formic acid or sodium formate. 
     
     
       19. The process of  claim 15 , wherein R 2  is alkyl or haloalkyl;
 R 1  is —C(O)OR 8  or —C(O)NR 9 R 10 ; and 
 R 3  is alkyl. 
 
     
     
       20. The process of  claim 15 , wherein in step (ii) the leaving group LG is iodide.